Fused indolecarboxamides: dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula:                    
     or the pharmaceutically acceptable acid addition salts thereof wherein:                    
     R 1  and R 2  are the same or different and represent hydrogen, C 1 -C 6  alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  alkoxy, —O 2 CR′, —NHCOR′, —COR′, —SO m R′, where R′ is C 1 -C 6  alkyl and wherein m is 0, 1 or  2 ; or 
     R 1  and R 2  independently represent —CONR′R″, or —NR′R″ where R′ and R″ independently represent hydrogen or C 1 -C 6  alkyl; 
     R 3  is hydrogen, C 1 -C 6  alkyl, or —COR′″ where R′″ is C 1 -C 6  alkyl; 
     R 4  is hydrogen or C 1 -C 6  alkyl; and 
     R represents an azacycloalkylalkyl group, 
     which compounds are useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer&#39;s disease, movement disorders such as Parkinsonism and dysronia, and other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorders. Further, compounds of this invention are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.

This application is a national phase application filed under 35 U.S.C.§371 of International Application PCT/US97/13973, filed Aug. 12, 1997,which is a continuation-in-part of U.S. application Ser. No. 08/695,712filed on Aug. 12, 1996, now U.S. Pat. No. 5,892,041.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to indolecarboxamide derivatives whichselectively bind to brain dopamine receptor subtypes. More specifically,it relates to fused indolecarboxamides such as carbozolecarboxamides,tetrahydrocarbazolecarboxamides, and fused cycloalkylindolecarboxamides,and to pharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in the treatment or prevention ofvarious neuropsychochological disorders such as schizophrenia and othercentral nervous system diseases.

2 Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₃ receptor subtype has recently beenidentified (Sokoloff et al., Nature, 347, 146 (1990)). Its uniquelocalization in limbic brain areas and its differential recognition ofvarious antipsychotics suggest that the D₃ receptor may play a majorrole in the etiology of schizophrenia. Selective D₃ antagonists may beeffective antipsychotics free from the neurological side effectsdisplayed by conventional neuroleptics. Compounds of the presentinvention demonstrate high affinity and selectivity in binding to the D₃receptor subtype. They may be of potential use in treatment ofschizophrenia, psychotic depression and mania. Other dopamine-mediateddiseases such as Parkinsonism and tardive dyskinesias may also betreated directly or indirectly by modulation of D₃ receptors.

U.S. Pat. No. 5,395,835 discloses N-aminoalkyl-2-napthalamides said tohave affinity at dopamine D₃ receptors. The compounds of the presentinvention differ significantly from this prior art in that they possessa dibenzofurancarboxamide substructure.

U.S. Pat. No. 3,932,456 discloses compounds of the formula:

wherein each of R₁ and R₂ is hydrogen, (lower)alkyl, cycloalkyl of 3 to6 ring carbon atoms, alkenyl of 3 to 6 carbon atoms having the vinylunsaturation in other than the 1-position of the alkenyl group, or R₁and R₂ taken together with the nitrogen atom to which they are attachedis pyrrolidino, piperidino, N-(lower) alkylpiperazino, or morpholino;each A is alkylene of 2 to about 8 carbon atoms and separates itsadjacent Y and amino nitrogen by an alkylene chain of at least 2 carbonatoms; each Y is oxygen, or N—R wherein R is hydrogen, methyl or ethyl;and R₃ is hydrogen or (lower) primary or secondary alkyl; or apharmaceutically acceptable acid addition salt thereof. These compoundsare said to be useful as pharmaceuticals for preventing or inhibiting aviral infection

International application WO94/14773 discloses compounds said to haveaffinity for the 5-HT₁-like receptor and utility in the treatment ofmigraine. The compounds disclosed in that application have the followingformula:

wherein R₁ represents halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, NO₂,—NR₄R₅, R₄R₅NCO(CH2)_(m)—, R₄R₅NSO₂(CH2)_(m)—, R₆CONH(CH2)_(m)—orR₇SO₂(CH2)_(m)—; R₄ and R₅ each independently represent hydrogen orC₁-C₄ alkyl or N₄R₅ represents a 5- to 7-member heterocyclic ring; R₆represents hydrogen or C₁-C₄ alkyl; R₇ represents C₁-C₄ alkyl; m iszero, 1, or 2; n is zero or 1 to 5; R₂ and R₃ each independentlyrepresent hydrogen, C₁-C₆ alkyl or benzyl or —NR₂R₃ represents apyrrolidino, piperidino or hexahydroazepino ring; and A represents abond, a C₁-C₅ alkylene chain or a C₁-C₅ alkenyl chain wherein the doublebond is not adjacent the nitrogen atom. Murray et al., Bioorg. Med.Chem. Let., 5: 219 (1995), describe 4carboxarnido-biphenyls said to haveaffinity at dopamine D₃ receptors.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdoparnine receptor subtypes. Thus, the invention provides compounds ofgeneral Formula I useful in the treatment and/or prevention of variousneuropsychological disorders. The invention also provides pharmaceuticalcompositions comprising compounds of Formula I.

The invention further relates to the use of such compounds andcompositions in the treatment of affective disorders such asschizophrenia, depression, Alzheimer's disease and certain movementdisorders such as Parkinsonism and dystonia. Compounds of this inventionare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents. Further, the compoundsof the present invention are useful for the treatment of other disorderswhich respond to dopaminergic blockade such as substance abuse andobsessive compulsive disorder.

Since dopamine D₃ receptors are concentrated in the limbic system(Taubes, Science, 265: 1034 (1994)) which controls cognition andemotion, compounds that interact with these receptors are also useful inthe treatment of cognitive disorders. Such disorders include cognitivedeficits which are a significant component of the negative symptoms(social withdrawal and unresponsiveness) of schizophrenia. Otherdisorders involving memory impairment or attention deficit disorders canalso be treated with the compounds of this invention which interactspecifically with the dopamine D₃ receptor subtype.

Furthermore, the compounds of this invention are useful in treatment ofdepression, memory-impairment or Alzheimer's disease by modulation of D₃receptors which selectively exist in limbic areas known to controlemotion and cognitive functions. The compounds of the present inventionare also useful for the treatment of other disorders that respond todopaminergic blockade such as substance abuse (Caine and Koob, Science,260: 1814 (1993)) and obsessive compulsive disorder (Goodman et al.,Clin. Psychopharmacol., 7: 35 (1992). The compounds of the inventioninteract with dopamine receptor subtypes resulting in thepharmacological activity of these compounds.

Accordingly, a broad embodiment of the invention is directed to acompound of Formula I:

or the pharmaceutically acceptable acid addition salts thereof; wherein:

where R_(a) and R_(b) independently represent hydrogen, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, or amino mono- or disubstituted with C₁-C₆ alkyl;and

n is an integer from one to four;

R₁ and R₂ are the same or different and represent hydrogen, C₁-C₆ alkyl,halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, C₁-C₆ alkoxy, —O₂CR′, —NHCOR′, —COR′, or —SO_(m)R′,where R′ is C₁-C₆ alkyl and where m is 0, 1 or 2; or

R₁ and R₂ independently represent —CONR′R″ or —NR′R″ where R′ and R″independently represent hydrogen or C₁-C₆ alkyl;

R₃ is hydrogen, C₁-C₆ alkyl, or —COR′″ where R′″ is C₁-C₆ alkyl;

R₄ is hydrogen or C₁-C₆ alkyl; and

R represents an azacycloalkylalkyl group.

Thus, the invention relates to the use of compounds of formula I in thetreatment and/or prevention of neuropsychochological disordersincluding, but not limited to, schizophrenia, mania, dementia,depression, anxiety, compulsive behavior, substance abuse, memoryimpairment, cognitive deficits, Parkinson-like motor disorders andmotion disorders related to the use of neuroleptic agents.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, theinvention encompasses compounds of general formula IA:

wherein

the A ring, R₁, R₂, R₃, and R₄ are as defined above for Formula I; and

R_(p) represents an azacycloalkylalkyl group of the formula

where

Q represents an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms;

Z is N or C;

R₅ and R₆ are the same or different and represent hydrogen or C₁-C₆alkyl; or

R₅ and R₆ together with the 6-membered ring to which they are attachedform a 5 to 8-membered ring; and

W is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or4-(1,2-dihydro)indenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl,benzofuranyl, or benzothienyl, each of which is optionally substitutedwith up to three groups independently selected from halogen, C₁-C₆alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamnino, cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of Formula IA include those where R₁ -R₄ arehydrogen or alkyl and Q is alkylene of 3-5 carbon atoms. Other preferredcompounds of Formula IA are those where R₁ and R₂ are hydrogen, R₃ ishydrogen or alkyl, more preferably hydrogen or methyl, R₄ is hydrogen,methyl, or ethyl, and Q is alkylene of 3-5 carbon atoms.

In addition to compounds of general Formula I described above, theinvention encompasses compounds of general Formula IB:

wherein:

the A ring and R₁-R₆ are as defined above for Formula IA; and

Q, Z and W are as defined above.

The present invention further encompasses compounds of Formula II:

where R_(a), R_(b), n, R_(p), and R₁-R₄ are as defined above for FormulaIA.

Preferred compounds of Formula II include those where R₁-R₄ are hydrogenor alkyl, R_(a) and R_(b) are hydrogen, and Q is alkylene of 3-5 carbonatoms. Other preferred compounds of Formula II are those where R_(a) andR_(b) are hydrogen, R₁ and R₂ are hydrogen, R₃ is hydrogen or alkyl,more preferably hydrogen or methyl, R₄ is hydrogen, methyl, or ethyl, Qis alkylene of 3-5 carbon atoms, more preferably butylene, and W isquinolinyl, naphthyl, or phenyl optionally substituted with up to twosubstituents independently selected from halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy. In more preferred compounds of Formula II, Z is nitrogen, and Wis quinolinyl, naphthyl, or phenyl optionally substituted with up to twogroups in the 2 and/or 3 positions (relative to the point of attachmentof the phenyl group to the piperazine ring), the groups beingindependently selected from halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy.Particularly preferred W groups of Formula II are those where W isnaphthyl or phenyl optionally substituted with up to two groups in the 2and/or 3 positions (relative to the point of attachment of the phenylgroup to the piperazine ring), the groups being independently selectedfrom chloro, methyl, and methoxy.

The present invention further encompasses compounds of Formula III:

where R_(a), R_(b), R_(p), and R₁-R₄ are as defined above for FormulaIA.

Preferred compounds of Formula III include those where R₁-R₄ arehydrogen or alkyl, R_(a) and R_(b) are hydrogen, and Q is alkylene of3-5 carbon atoms. Other preferred compounds of Formula III are thosewhere R_(a) and R_(b) are hydrogen, R₁ and R₂ are hydrogen, R₃ ishydrogen or alkyl, more preferably hydrogen or methyl, R₄ is hydrogen,methyl, or ethyl, Q is alkylene of 3-5 carbon atoms, more preferablybutylene, and W is quinolinyl, naphthyl, or phenyl optionallysubstituted with up to two substituents independently selected fromhalogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy. In more preferred compounds ofFormula III, Z is nitrogen, and W is quinolinyl, naphthyl or phenyloptionally substituted with up to two groups in the 2 and/or 3 positions(relative to the point of attachment of the phenyl group to thepiperazine ring), the groups being independently selected from halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy. Particularly preferred W groups ofFormula III are those where W is naphthyl or phenyl optionallysubstituted with up to two groups in the 2 and/or 3 positions (relativeto the point of attachment of the phenyl group to the piperazine ring),the groups being independently selected from chloro, methyl, andmethoxy.

The invention also provides compounds of Formula IV

where R_(a), R_(b), R_(p), and R₁-R₄ are as defined above for FormulaIA.

Preferred compounds of Formula IV include those where R₁ -R₄ arehydrogen or alkyl, R_(a) and R_(b) are hydrogen, and Q is alkylene of3-5 carbon atoms. Other preferred compounds of Formula IV are thosewhere R_(a) and R_(b) are hydrogen, R₁ and R₂ are hydrogen, R₃ ishydrogen or alkyl, more preferably hydrogen or methyl, R₄ is hydrogen,methyl, or ethyl, Q is alkylene of 3-5 carbon atoms, more preferablybutylene, and W is quinolinyl, naphthyl, or phenyl optionallysubstituted with up to two substituents independently selected fromhalogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy. In more preferred compounds ofFormula IV, Z is nitrogen, and W is quinolinyl, naphthyl or phenyloptionally substituted with up to two groups in the 2 and/or 3 positions(relative to the point of attachment of the phenyl group to thepiperazine ring), the groups being independently selected from halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy. Particularly preferred W groups ofFormula IV are those where W is naphthyl or phenyl optionallysubstituted with up to two groups in the 2 and/or 3 positions (relativeto the point of attachment of the phenyl group to the piperazine ring),the groups being independently selected from chloro, methyl, andmethoxy.

When a compound of the invention is obtained as a mixture ofenantiomers, these enantiomers can be separated, when desired, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, for example using a chiral HPLCcolumn.

Representative compounds of the present invention, which are encompassedby Formula I. include, but are not limited to, the compounds shown inTable 1 below and their pharmaceutically acceptable salts. Non-toxicpharmaceutically acceptable salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, fonnic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses prodrugs, e.g., acylatedprodrugs, of the compounds of Formula I. Those skilled in the art willrecognize various synthetic methodologies which may be employed toprepare non-toxic pharmaceutically acceptable addition salts andprodrugs of the compounds encompassed by Formula I.

The following numbering system is used to identify positions on thecarbazole ring portion of the compounds of the invention:

The following numbering system is used to identify positions on thetetrahydrocarbazole-ring portion of the compounds of the invention:

The following numbering system is used to identify positions on thetetrahydrocyclopeiit[b]indole ring portion of the compounds of theinvention:

The following numbering system is used to identify positions on thehexahydrocvclohcpt[b]indole ring portion of the compounds of theinvention:

By “alkyl” and “lower alkyl” is meant straight or branched chain alkylgroups having from 1-6 carbon atoms, e.g., C₁-C₆ alkyl.

By “lower alkoxy” and “alkoxy” is meant straight or branched chainalkoxy groups having from 1-6 carbon atoms, e.g., C₁-C₆ alkoxy.

By halogen is meant an atom of fluorine, chlorine, bromine or iodine.

By azacycloalkylalkyl is meant an azacycloalkyl moiety, e.g., piperazineor piperidine, linked via a nitrogen atom to an alkylene group, e.g.,methylene, ethylene, or butylene. Where the azacycloalkyl portion ispiperazine and the alkylene group is butylene, the resulting group is apiperazinylbutyl group. Such a group has the formula:

The azacycloalkyl group represented by R_(p) above includes groupsrepresented by the formula T

where Z and W are defined above.

The formula T represents saturated heterocyclic ring systems such as,for example, piperidinyl and piperazinyl, as well as unsaturatedheterocyclic ring systems such as, for example,1,2,3,6-tetrahydropyrinine. Preferred T groups are the following:

where W is defined above.

Particularly preferred W groups of the invention are quinolinyl,naphthyl, or phenyl optionally substituted with up to two substituentsindependently selected from halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy.These optional phenyl substituents are preferably in the 2 and/or 3positions of the phenyl group relative to the point of attachment of thephenyl group to the 6-membered nitrogen containing ring.

The azacycloalkyl group represented by R_(p) also encompasses groups ofthe formula:

where Z and W are defined above and R₅ and R₆ together with the6-membered ring to which they are attached form a 5 to 8-membered ring.In such cases, and where Z is nitrogen, the resulting group is adiazabicyclo group. Examples include 3,8-diazabicyclo[3.2.1]octane,3,9-diazabicyclo[3.3.1]nonane, 2,5-diazabicyclo[2.2.2]octane,7.9-diazabicyclo[4.2.2]decane, and 3,9-diazabicyclo[3.3.1]nonane.

Representative examples of fused indolecarboxamides according to theinvention are shown in Table 1 below. The number below each compound isits compound number. Each of these compounds may be prepared accordingto the general reaction scheme set forth below.

The compounds in Table 1 have the following general Formula A:

where R_(c) and R_(d) independently represent hydrogen or a group of theformula

R, R₃, and R₄ are defined in the table.

TABLE 1 Comound Number A R_(c) R_(d) R₃ R 1

H

H

2

H

H

3

H

CH₃

4

H H

5

H CH₃

6

H

H

7

H

H

8

H H

9

H

CH₃

10 

H H

The invention also pertains to the use of compounds of general Formula Iin the treatment of neuropsychological disorders. The pharmaceuticalutility of compounds of this invention are indicated by the followingassays for dopamine receptor subtype affinity.

ASSAY FOR D₂ AND D₃ RECEPTOR BINDING ACTIVITY

Pellets of COS cells containing recombinantly produced D₂ or D₃receptors from African Green monkey were used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and pH 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenized. The sample is then centrifuged as described and thefinal tissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³H-YM 09151-2 and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 1 mM spiperone; without further additions,nonspecific binding is less than 20% of total binding. The bindingcharacteristics of representative compounds of the invention for D₂ andD₃ receptor subtypes are shown in Table 2 for rat striatal homogenates.

TABLE 2 Compound Number¹ D₃ K_(i) (nM) D₂ K_(i) (nM) 1 0.5 250 3 2 540 41 750 ¹Compound numbers relate to compounds shown above in Table 1.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe and partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds general Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preparation of N-aminoalkyldibenzofurancarboxamides

The compounds of the invention and their corresponding pharmaceuticallyacceptable acid addition salts thereof may be prepared according to thereactions shown below in the following schemes.

The compounds of Formula I may be prepared by a process which comprisesreacting a compound of Formula V with a compound of Formula VI as shownbelow:

wherein R₁, R₂, R₃, R₄, R₅, A, Q, Z and W are defined as above forFormula I.

A compound of Formula V may be activated with a reagent such as1,1′-carbonyldiimidazole (CDI) or the like in a solvent such astetrahydrofuran or the like at room temperature. The resulting activatedcarboxylate intermediate may be subsequently reacted with a compound ofFormula VI to afford a compound of Formula I as the desired product.

A compound of Formula Va

wherein R_(a), R_(b), R₁, R₂ and n are defined as above, may be preparedby reacting a compound of Formula Va1 with a compound of Formula Va2 viathe Fischer indole synthesis as shown below:

wherein R_(a), R_(b), R₁, R₂ and n are defined as above.

The reaction may be carried out according to procedures well describedin the literature. For example, see Robinson, “The Fischer IndoleSynthesis”, Wiley, N.Y., 1983. Preferably, the reaction is carried outin the presence of acetic acid under reflux for about four hours.

In the case where n is 2, a compound of Formula Va3 may be prepared asdepicted in the scheme below by dehydrogenation of a compound of FormulaVa in a refluxing solvent such as xylene or the like in the presence ofa catalyst such as, for example, palladium on carbon. Preferably, thereaction is carried out with 10% palladium on carbon in xylene at refluxfor about eight hours.

Similarly, a compound of Formula Vb

wherein R_(a) and R_(b) are defined as above for Formula I, may beprepared by dehydrogenation of a compound of Formula Vb1 as shown in thebelow scheme in a refluxing solvent such as, for example, xylene, in thepresence of a catalyst such as palladium on carbon or the like.Preferably, the reaction is carried out with 10% palladium on carbon inxylene at reflux for about eight hours.

Further, a compound of Formula Vb1

wherein R_(a) and R_(b) are defined as above for Formula I, may beprepared by reacting a compound of Formula Vb2 with a compound ofFormula Vb3 via the Fischer indole synthesis as represented below:

wherein R_(a) and R_(b) are defined as above for Formula I. The reactionmay be carried out according to well known literature procedures. See,for example, Robinson, “The Fischer Indole Synthesis”, Wiley, N.Y.,1983. Preferably, the above reaction is carried out in the presence ofacetic acid (HOAC) under reflux for about 4 hours.

A compound of Formula V

wherein R₁, R₂ and A are defined as above and R₃ is hydrogen, may beprepared by methods analogous to those described above for Formula Va orthose for Formula Vb.

Where R₃ is not hydrogen, a compound of Formula V may be prepared byreacting a compound of Formula Vc1

wherein R₁, R₂ and A are defined as above with a halide of the formula:R₃-X, where R₃ is defined as above for Formula I and X is a ride. Thereaction is normally carried out in the presence of a base such as, forexample, K₂CO₃ in a solvent such as acetone or the like at roomtemperature. Subsequently, the resulting intermediate may be hydrolyzedwith a base such as NaOH or the like in an aqueous solvent such asmethanol at about 50° C. to afford a compound of Formula V. Preferably,the reaction is carried out with K₂CO₃ in acetone, and the hydrolysis iscarried out with NaOH in aqueous methanol.

Where they are not commercially available, the compounds of Formula Va1,Formula V2, Formula Vb2 and Formula Vb3 may be prepared by proceduresanalogous to these described in literature. Compounds of Formula VIoften can be obtained from commercial sources. Alternatively, suchcompounds are known compounds or are capable of being prepared byliterature methods.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. In some cases, protection of certain reactive functionalitiesmay be necessary to achieve some of the above trasformations. Ingeneral, the need for such protecting groups will be apparent to thoseskill in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them. These examples illustrate thepresently preferred methods for preparing the compounds of theinvention.

EXAMPLE 1

1. 1,2,3,4-tetrahydrocarbazole-6-carboxylic acid

A mixture of 4-hydrazinobenzoic acid (5.0 g, 32.9 mmol) andcyclohexanone (3.3 g, 33 mmol) in 30 mL of acetic acid was heated underreflux for 4 hours, then cooled, diluted with water and acidified withHCl. The resultant solid was collected by filtration, washed with waterand dried to give 3.6 g of the title compound as a crystalline solid.

2.N-(1-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydrocarbazole-6-carboxamidehydrochloride

A mixture of 1,2,3,4-tetrahyrocarbazole-6-carboxylic acid (100 mg, 0.46mmol) and 1,1′-carbonyldiimidazole (78 mg, 0.48 mmol) in 5 mL ofanhydrous tetrahydrofliran was stirred for 8 hours. A solution of4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-1-aminobutane (140 mg, 0.46mmol) in 1 mL of tetrahydrofuran was added and the resulting mixture wasstirred for 30 minutes. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with aqueousNa₂CO₃ solution, dried (Na₂SO₄) and concentrated in vacuo to afford thefree base of the title compound,N-(1-{4-[4-2,3-dichlorophenyl)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydrocarbazole-6carboxamide,(161 mg, 70%). The hydrochloride salt was prepared by treating the freebase with a solution of hydrogen chloride in ethyl acetate (mp 236-238°C.).

EXAMPLE 2

The following compounds are prepared essentially according to theprocedures set forth in Example 1 above.

(a)N-(1-{4-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydrocarbazole-6-carboxamidehydrochloride (mp 229-231° C.)

(b)N-(1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydrocarbazole-6-carboxamidehydrochloride (mp 224-226° C.)

(c)N-(1-{4-[4-(1-Naphthyl)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydrocarbazole-6-carboxamidehydrochloride (mp 207-210° C.)

(d)N-(1-{4-[4-(2,3-Dichloropheny)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydrocyclopent[b]indole-7-carboxamidehydrochloride (Compound 6, mp 224-226° C.)

(e)N-(1-{4-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydro-cyclopent[b]indole-7-carboxamidehydrochloride (mp 231-233° C.)

(f)N-(1-{4-[4-(2,3-Dichloropheny)piperazin-1-yl]}butyl)-5,6,7,8,9,10-hexahydro-cyclohept[b]indole-2-carboxamide(Compound 7, mp 212-214° C.)

EXAMPLE 3

1. Preparation of 9H-carbazole-3-carboxylic acid.

A suspension of 1,2,3,4-tetrahydrocarbazole-6-carboxylic acid (1.0 g,4.6 mmol) and 10% Pd/C (0.7 g) in 50 mL of xylene was heated underreflux for 8 hours. The hot reaction mixture was filtered throughcelite. The filtrate was concentrated in vacuo to give the titlecompound (0.8 g, 80%).

2.N-(1-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]}butyl)-9H-carbazole-3-carboxamidehydrochloride

A mixture of 9H-carbazole-3-carboxylic acid (50 mg, 0.23 mmol) and1,1′-carbonyldiimidazole (39 mg, 0.24 mmol) in 5 mL of anhydroustetrahydrofuran was stirred for 8 hours. A solution of4-[4-(2,3,-dichlorophenyl)piperazin-1-yl]-1-aminobutane (70 mg, 0.23mmol) in 1 mL of tetrahydrofuran was added and the resulting mixture wasstirred for 30 minutes. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with aqueousNa₂CO₃ solution, dried (Na₂SO₄) and concentrated in vacuo to give thetitle compound (85 mg, 72%). The hydrochloride salt was prepared bytreating the free base with a solution of hydrogen chloride in ethylacetate (mp 214-216° C.).

EXAMPLE 4

The following compounds are prepared essentially according to theprocedures set forth above in EXAMPLE 3.

(a)N-(1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]}butyl)-9H-carbazole-3-carboxamidehydrochloride (mp 218-220° C.)

(b)N-(1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]}butyl)-9H-carbazole-3-carboxamidehydrochloride (mp 225-227° C.)

EXAMPLE 5

1. 1,2,3,4-tetrahydrocarbazole-2-carboxylic acid

A mixture of 3-ketocyclohexanecarboxlic acid (4.78 g, 33.9 mmol) andphenyihydrazine (3.66 g, 40 mmol) in 35 mL of acetic acid was heatedunder reflux for one hour, then cooled, diluted with water and acidifiedwith HCl. The resultant solid was collected by filtration, washed withwater and dried to give 5.5 g of the title compound as a crystallinesolid.

2. 9H-carbazole-2-carboxylic acid

A suspension of 1,2,3,4-tetrahydrocarazole-2-carboxylic acid (0.6 g, 2.8mmol) and 10% Pd/C (0.5 g) in 30 mL of xylene was heated under refluxfor 8 hours. The hot reaction mixture was filtered through celite. Thefiltrate was concentrated in vacuo to give the title compound (0.5 g,85%)

3.N-(1-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]}butyl)-9H-carbazole-2-carboxamidehydrochloride

A mixture of 9H-carbazole-2-carboxylic acid (50 mg, 0.23 mmol) and1,1′-carbonyldiimidazole (39 mg, 0.24 mmol) in 5 mL of anhydroustetrahydrofuran was stirred for 8 hours. A solution of4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-1-aminobutane (70 mg, 0.23mmol) in 1 mL of tetrahydrofuran was added and the resulting mixture wasstirred for 30 minutes. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with aqueousNa₂CO₃ solution. dried (Na₂SO₄) and concentrated in vacuo to give thetitle compound (75 mg, 64%). The hydrochloride salt was prepared bytreating the free base with a solution of hydrogen chloride in ethylacetate (mp 240-241° C.).

EXAMPLE 6

The following compounds are prepared essentially according to theprocedures set forth above in Example 5.

(a)N-(1-{4-[4-(2,3-Methylphenyl)piperazin-1-yl]}butyl)-9H-carbazole-2-carboxamidehydrochloride (Compound 8, mp 250-253° C.)

(b)N-(1-{4-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]}butyl)-9H-carbazole-2-carboxamidehydrochloride (Compound 10, mp 246-248° C.)

EXAMPLE 7

1. 9-methylcarbazole-3-carboxylic acid

A mixture of 9H-carbazole-3-carboxylic acid (300 mg, 1.42 mmol), K₂CO₃(800 mg) and methyl iodide (1 mL) in 25 mL of acetone was heated underreflux overnight, then cooled and evaporated in vacuo. A mixture of theresultant residue and NaOH (170 mg) in aqueous MeOH (90%, 25 mL) wasstirred at 50° C. for 30 minutes. The reaction mixture was concentratedand acidified with diluted HCl. The solids were collected by filtrationand dried to give the title compound (280 mg, 87%).

2.N-(1-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]}butyl)-9methylcarbazole-3-carboxamidehydrochloride

A mixture of 9H-carbazole-2-carboxylic acid (50 mg, 0.23 mmol) and1,1′-carbonyldiimidazole (39 mg, 0.24 mmol) in 5 mL of anhydroustetrahydrofuran was stirred for 8 hours. A solution of4-[4-(2,3,-dichlorophenyl)piperazin-1-yl]-1-aminobutane (70 mg, 0.23mmol) in 1 mL of tetrahydrofuran was added and the resulting mixture wasstirred for 30 minutes. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with aqueousNa₂CO₃ solution. dried (Na₂SO₄) and concentrated in vacuo to give thetitle compound (80 mg, 68%). The hydrochloride salt was prepared bytreating the free base with a solution of hydrogen chloride in ethylacetate (mp 237-239° C.).

EXAMPLE 8

The following compounds are prepared essentially according to theprocedures set forth above in Example 7.

(a)N-(1-{4-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]}butyl)-9methylcarbazole-3-carboxamidehydrochloride (mp 224-226° C.)

(b)N-(1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]}butyl)-9-methylcarbazole-2-carboxamidehydrochloride (Compound 5, mp 276-78° C.)

(c)N-(1-{4-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]}butyl)-9-methylcarbazole-2-carboxamidehydrochloride (Compound 9, mp 269-271° C.)

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. compound of the formula:

n is an integer from one to four; R₃ is hydrogen or C₁-C₆ alkyl; R₄ ishydrogen or C₁-C₆ alkyl; and R_(p) represents a structure of the formula

where Q representi an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms; W is phenyl or naphthyl, each of which is optionally substitutedwith up to three groups independently selected from halogen, C₁-C₆alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
 2. Acompound of the formula:

wherein n is an integer from one to three; R₃ is hydrogen or C₁-C₆alkyl; R₄ is hydrogen or C₁-C₆ alkyl; and R_(p) represents a structureof the formula

where Q represents an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms; and W is phenyl or naphthyl, each of which is optionallysubstituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
 3. Acompound according to claim 2, which is:

where W is naphthyl or W is phenyl optionally substituted with up to 3groups independently selected from halogen, C₁-C₆ alkyl, and C₁-C₆alkoxy.
 4. A compound of the formula:

wherein R₃ is hydrogen or C₁-C₆ alkyl; R₄ is hydrogen or C₁-C₆ alkyl;and R_(p) represents a structure of the formula

where Q represents an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms; and W is phenyl or naphthyl, each of which is optionallysubsituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkqxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
 5. Acompound according to claim 4, which is:

where W is naphthyl or W is phenyl optionally substituted with up to 3groups independently selected from halogen, C₁-C₆ alkyl, and C₁-C₆alkoxy.
 6. A compound of the formula:

wherein R₃ is hydrogen or C₁-C₆ alkyl; R₄ is hydrogen or C₁-C₆ alkyl;and R_(p) represents a structure of the formula

where Q represents an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms; and W is phenyl or naphthyl; each of which is optionallysubsituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkqxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
 7. Acompound according to claim 6, which is:

where W is naphthyl or W is phenyl optionally substituted with up to 3groups independently selected from halogen, C₁-C₆ alkyl, and C₁-C₆alkoxy.